The role of the Na⁺/H⁺ exchanger in rat hearts during ischemia and reperfusion was investigated by measurements of intracellular Na⁺ concentration ([Na⁺]_i) and intracellular and extracellular pH. Under our standard conditions (2-Hz stimulation), 10 min of ischemia caused no significant rise in [Na⁺]_i but an acidosis of 1.0 pH unit, suggesting that the Na⁺/H⁺ exchanger was inactive during ischemia. This was confirmed by showing that the Na⁺/H⁺ exchange inhibitor methylisobutyl amiloride (MIA) had no effect on [Na⁺]_i or on intracellular pH during ischemia. However, there was a short-lived increase in [Na⁺]_i of 8.2 ± 0.6 mM on reperfusion, which was reduced by MIA, showing that the Na⁺/H⁺ exchanger became active on reperfusion. To investigate the role of metabolic changes, we measured [Na⁺]_i during anoxia. The [Na⁺]_i did not change during 10 min of anoxia, but there was a small, transient rise of [Na⁺]_i on reoxygenation, which was inhibited by MIA. In addition, we show that the Na⁺/H⁺ exchanger, tested by sodium lactate exposure, was inhibited during anoxia. These results show that the Na⁺/H⁺ exchanger is inhibited during ischemia and anoxia, probably by an intracellular metabolic mechanism. The exchanger activates rapidly on reperfusion and can cause a rapid rise in [Na⁺]_i.

ischemia-reperfusion; methylisobutyl amiloride

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